The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Medicinal antioxidants are compounds that may be used for the prevention of tissue damage induced by lipid peroxidation (Halliwell, B., FASEB J 1:358–364, 1987). During lipid peroxidation free radicals interact with polyunsaturated fatty acids to form lipid peroxyl radicals, which produce lipid hydroperoxides and further lipid peroxyl radicals. This peroxidative cascade may eventually consume an essential part of the membrane lipid, which may lead to changes in membrane permeability and ultimately in cell death. The peroxidative degradation of lipids also leads to the formation of potentially toxic products such as malondialdehyde.
U.S. Pat. No. 5,929,123 discloses the use of halogenated triphenylethylene derivatives for lowering levels of serum lipid peroxides and for treatment or prevention of oxidative tissue damages induced by lipid peroxidation.
Hydroxymatairesinol and matairesinol are both plant lignanes and they have been disclosed to possess various beneficial therapeutical effects.
E. Yesilada et al. (Cytokine 13:359–364, 2001) disclose the use of certain compounds, i.e., matairesinol, to decrease tumour necrosis factor alpha (TNF-α) production and the anti-inflammatory activity of the compounds.
The International Patent Application WO 00/59946, assigned to Hormos Nutraceutical Oy Ltd, discloses hydroxymatairesinol as an inhibitor of lipid peroxidation and LDL oxidation, and thus its usefulness as an antioxidant.
The above publications do not, however, disclose the ability of any agent to cause a decrease in the formation of reactive oxygen species which cause the lipid oxidation.
After specific membrane perturbation by either particulate or soluble stimuli, neutrophilic granulocytes (neutrophils) exhibit a burst in oxygen consumption (called the respiratory or oxidative burst). The oxygen consumed is not used in cellular respiration, but is converted primarily to superoxide and hydrogen peroxide. The heme protein myeloperoxidase uses hydrogen peroxide to convert chloride to hypochlorous acid and to convert L-tyrosine to tyrosyl radical. Generation of reactive oxygen species, hypochlorous acid and tyrosyl radical together form the basis of microbicidical action of human neutrophils (FIG. 1). The function of oxidative burst and formation of reactive species have been observed not only in neutrophils, but also in macrophages, microglial cells of the brain, the Kupffer cells of the liver, monocytes, basophils, mast cells, and eosinophils.
Besides the microbicidical action, reactive species generated by the oxidative burst and myeloperoxidase may cause damage to molecules and cellular components of the host organism (FIG. 1). Prolonged overactivity of reactive species generating cell types results in sustained oxidative stress and, hence, tissue damage. Such an overactivity may typically be encountered in a variety of either acute (e.g. ischemia-reperfusion injury in myocardial infarction, stroke and transplantation, and adult respiratory distress syndrome) or chronic (rheumatoid arthritis, asthma, inflammatory bowel disease, HIV, psoriasis and inflammatory conditions of the skin) inflammatory conditions. It is now well known that in addition to the physiological ageing, reactive oxygen species are implicated in the pathophysiology of numerous human diseases.
Attempts to control adverse implications of overactive cellular defence functions have been largely focused on migration, binding and tissue infiltration of these cells. However, since the reactive species produced by oxidative burst and myeloperoxidase are the ultimate damaging agents, it seems logical that a more direct way for attenuation of the damage due to over-activity would be effective inhibition of oxidative burst and myeloperoxidase activity.
Upon allergic and autoimmune reactions and viral infections, lymphocytes (or T-cells) activate and they can act in target tissues by augmenting immune response indirectly by activating other cells such as macrophages and B cells (helper T-cells), or by killing cells infected with viruses directly (cytotoxic T-cells). The recognition of specific antigens by specific T-cell receptors, leads to clonal expansion of specific T-cell population and generation of an adaptive immune response. Autoimmune disease occurs when this adaptive response is initiated against self-antigens.
Extended and persistent autoimmune responses are disadvantageous since they manifest diseases including rheumathoid arthritis and inflammatory bowel disease. They also contribute to allergic reactions and asthma. Therefore, timely termination of this response is essential.
After completion of their mission, T-cells are eliminated through programmed cell death, or apoptosis. An important messenger molecule mediating this self-destruction is a 319 aminoacid transmembrane glycoprotein Fas (also known as Apo 1 or CD95). Fas belongs to tumour necrosis factor receptor superfamily (Itoh et al., Cell 66:233–43, 1991). When engaged by its ligand, FasL, it generates a sequential activation of a cascade of intracellular serine proteases, called caspases, leading to destruction of cellular architecture and degradation of DNA by endonucleases.
Resting T-cells express little Fas on the cell surface. After T-cell stimulation (by e.g., T cell receptor), Fas-expression is increased and the T-cells become sensitive to Fas-mediated death (triggered through autocrine and paracrine production of FasL after T cell receptor stimulation). Thus, Fas-FasL system represents an highly important mechanism is regulating T-cell homeostasis.
TNF-α is a pro-inflammatory cytokine that is involved in the pathogenesis of several inflammatory diseases. Blockade of TNF-α has been shown to be useful in the treatment of chronic inflammatory conditions, such as rheumatoid arthritis and Crohn's disease (Flier, J. S. and Underhill, L. H, “The tumor necrosis factor ligand and receptor families”, New Eng. J Med. 334:1717–1725, 1996).